Our long-term objective is to identify how protein conformation plays a role in various diseases. Our specific aims are to compute the 3D structures of proteins, protein-protein and protein-nucleic acid complexes, and the folding pathways leading to these entities, using a hierarchical physics-based method. Extensive conformational search is performed with our united-residue (UNRES) force field, in which a polypeptide chain is represented as a virtual-bond C(alpha)-C(alpha) and C(alpha)-SC chain, and the resulting conformations are converted to an all-atom representation and refined at the all-atom level. UNRES has been derived as a restricted free energy function of united-residue chains averaged over the degrees of freedom that are lost when passing to the virtual-bond geometry. Kubo's cluster cumulant theory has been used to derive analytical expressions for the respective free-energy terms, which enabled us to express the multibody terms analytically, which are essential for reproducing regular alpha-helical and beta-sheet structures. Our approach was successful in two recent blind protein structure prediction tests: CASP5 and CASP6; we predicted complete structures of four targets of which two were alpha-helical and two were alpha/beta proteins, and large segments of other targets. We made a start on predicting folding pathways by implementing Langevin dynamics for the UNRES force field. Using UNRES/MD, we folded a 75-residue protein from the extended conformation to the native structure in about 5 hours on a single processor; this means that UNRES/MD provides a 10,000 fold increase in the time scale compared to all-atom MD and is a practical method for studying protein-folding pathways up to the millisecond scale. The UNRES/MD approach, however, suffers from the neglect of configurational entropy in the present parameterization. We will rectify this deficiency by revising the parameterization of UNRES. We will also further develop: (a) our global-optimization algorithms by replacing local minimization with short MD runs, thereby incorporating configurational entropy, (b) our all-atom force field, and (c) a method to convert UNRES folding pathways to all-atom pathways. We will also extend the UNRES approach to derive a united-residue physics-based force field to study protein-nucleic acid interactions. [unreadable] [unreadable] [unreadable]